Alpha-(aminoalkyl)-stilbenes



Patented Oct. 25, 1949 UNITED STATES PATENT OFFICE anrmi- 'arnuzm -smnamEwald Bolu'mann, Indianapolis, Ind., l-iml' to Eli Lilly and Company.

corporation of Indiana No Drawing. Application April 13, 1948,

, Serial N0. 2.,831

1 My invention relates to novel organic compounds and more particularlyto substituted stilbenes and their acid addition salts.

The bases of the stilbene compounds of my invention may be representedby the formula a-(2-piperidinoethyl) -stilbene hydrochloride, which maybe represented by the formula a. (2 methyl 2diethylaminoethy1)-4'-isopropyl stilbene hydrobromide, which may berepresented by the formula {as r -4D C 1 H H #13,

Additional examples of stilbene compounds are a(2-piperidinoethyi)-4-methoxystilbene, a-(2- morpholinoethyl) stilbene,a-(2-methylamino- Indianapolis, Ind, a

1 cum. (cum-29:)

ethyl) -stilbene, a-(z-piperidinoethyl) -4-chlorostilbene, a(2-piperidinoethyl-4'-chlorostilbene, a-(z-ethylaminoethyl) -stilbene,a-(2-piperidinoethyl) 4 methylstilbene, a(Z-methylpropylaminoethyD-stilbene, a (z-piperidinoethyl) -2'-chlorostilbene, a- (2-piperidinoethyl) -3'-methylstilbene, a(Z-piperidinoethyl)-4'-isopropylstilbene, a-(2-piperidinoethyl)-2'-methylstilbene, a- (Z-plperidinoethyl) -4'-methylstilbene,a-methylaminoethylstilbene, (3-dimethylaminopropyl) 4'-bromostilbene,and a.-(2-piperidinopropyl)-2- butylstilbene. I

The bases of my novel stilbene compounds are colorless, low-meltingsolids or oils, and are soluble in the common organic solvents andinsoluble in water. Because of the basic group contained in the novelcompounds, acid addition salts may be formed with acids. Thus, salts ofthe bases may be formed from mineral acids, such as hydrochloric,hydrobromic, phosphoric and sulfuric acids, and-such salts exhibit watersolubility. Likewise, salts of the bases may be formed from organicacids, such as acetic, maleic, cinnamic, stearic and oleic acids. Saltsprepared from organic acids having a relatively great number of carbonatoms, for example oleic acid, are characterized by a slightwater-solubility and an appreciable solubility in oils.

The novel compounds of my invention exhibit activity as antihistaminicagents.

The preparation of the novel compounds of my invention is accomplishedin the follow manner: Broadly speaking, three steps are involved. First,an aminoketone is prepared by the Mannich reaction by interreactingformaldehyde, an acylalkyl ketone wherein the acyl radical correspondsto the R: substituent desired in-the final compound, and an amine havinga radical corresponding to the Rs substituent. Second, the aminoketoneis converted to a carbinol by treating it with a Grignard reagent formedfrom a benzyl halide wherein the phenyl group in the benzyl halidecorresponds to the desired R1 substituent. Finally, the carbinol isconverted to an acid addition salt of the substituted stilbene by meansof a dehydrating agent such as concentrated hydrochloric acid or otheracidic dehydrating agent, for example, hydrobromic acid, phosphorustribromide, phosphorus oxychloride, and the like. The acid addition saltmay be converted to the free base by known methods, e. g. treatment withalkali.

By way of illustration of the above-described process, the chemicaltransformations which take place in the production ofc-(2-piperidinoethyl) -4-methoxystilbene hydrochloride and its memos 3 4free base are represented by the following equathe compounds correspondto the general formula tions. These equatlonagtypify the general courseset out at the head or the table and the various 0! the reactionsinvolved in the production oi the substituents are indicated in thecolumns under stilbene compounds or thisginvention. the respectiveheadings. The melting points and n 0-0 ocn on o oc-o on Ha 11H: i

/ a Ha & H: t H9 330 CEQ Hai 41 H MgCl O a I OH @E-iQ @rgQ Substitutedstilbenes prepared by the methods analytic results given in the tableare for the salt described are illustrated in Table I. In the table, orbase as indicated.

TABLE I B -C=CB3 Analfisis Per Cent N in ried Sample B R; x R: M. P. ofSalt Calc'd Found ZOHs-CQ --(cH, N\ on, 240-244" 0., no]-.. 4. z; 4. m

CHI-C CHI-CH CHaO -d0-.--.-. CH1 244-35" 0., HCL. 4. l7 4. 66

CHr-C:

GH -CH3 -.d0.. 0 W24? (1., HC].... 4. 24 4.43

CH -C CHr-CH 01 .....d0....... CH1 $17-33" 0., BBL.-- 3. 44 3. 88

CHr-Cg CHr-CH, Cl ----.d0 CH: 207-2us.5 0., H31... 3. 44 3. 68

OKs-C Analysis Per Cent N inDrled Sample R1 R, x In M. P.0iSelt CalcdFound CIHI Q- -(c1n)r--.. N\ oil free base 4.77 3.99

CiHs

.CHr-CH:

on ....do N\ CH: 24oo.,no1 4.10 4.08

cm-cfi,

CH: Q- do N\ 167-168 0., REL--- 3.89 3.91

can CHg-CE: do N\ on, new 0., HBL... 3.36 3.35 l CHg-C 3 GHQ-CH: do Yon, l83-184C.,HBr. 3.03 4.25

CHr-C 1 CH: CHg-CH,

do. -N\ on, 207-208C.,HBr. 3.38 3.28 C CHr-Cfi:

cur-0H,

----do---- N CH: 208209C.,HBr 0:68.38 0:68.38 H=6.98 H=7.24

CHr- H: H:

GHQ-CH2 CHQ- -----do -i'-r CH: 209-2l0C.,HBr- 3.63 3.61

cu -c The following examples illustrate with greater particularity thepreparation of the compounds of my invention.

Example 1 Preparation of a-(2-piperidinoethyl) -stilbene hydrochloride.

Phenyl-(p-plperidino) -ethyl ketone hydrochloride is prepared accordingto the method of Mannich and Lammering, Ber. 55, 3510, 1923, byrefluxing for one hour a mixture of 122 g. (1 mol) of piperidinehydrochloride, 45 g. (1.5 mols) of paraformaldehyde, 2.5 cc. of 12Nhydrochloric acid, 300 cc. of absolute ethanol and 120 g. (1 mol) ofacetophenone. g. (1 mol) of paraformaldehyde are then added andrefluxing is continued for 2 hours. To the hot mixture are added 250 cc.of boiling acetone, and the resulting solution is allowed to cool slowlyand finally is cooled in an ice bath, whereupon a while crystallineprecipitate of phenyl-fl-piperldinoethyl ketone hydrochloride forms. Theprecipitate is filtered off and recrystallized by dissolving it in aminimum amount of hot ethanol, diluting the ethanol solution withseveral volumes of boiling acetone, and cooling.Phenyl-fi-piperidinoethyl ketone hydrochloride melting at about 192-193C. is thus obtained. The free base is prepared from the salt bydissolving the phenyl-p-piperidinoethyl ketone hydrochloride in water,adding concentrated sodium hydroxide solution until alkaline, andextracting the phenyl-fl-piperldino ketone with ether. The ether extractis dried over anhydrous magnesium sulfate and potassium carbonate. Theresulting anhydrous ether solutlon of phenyl-p-piperidinoethyl ketonecan be used directly for subsequent operations, or if desired. can bedistilled in vacuo to yield the free base as an oil.

a-Phenyl m (2-piperidinoethyl) B phenylethanol hydrochloride is preparedfrom the phenyl p-piperidinoethyl ketone as follows:

A Grlgnard reagent is prepared from 17 g. (0.7 mol) of magnesium and g.(0.7 mol) of benzyl chloride in 500 cc. of anhydrous ether. To thisreagent are slowly added with stirring 200 cc. of dry ether containing69 g. (0.32 mol) of phenyl p-piperidlnoethyl ketone. After stirring for2 hours the mixture is treated with 170 cc. of concentrated hydrochloricacid and g. of ice. A white solid comprisinga-phenyI-Q-(Z-piperidinoethyl) -;8-phenylethanol hydrochloride separatesand is filtered off. The solid is washed with a small amount of icewater and recrystallized from aqueous acetone.a-Phenyl-u-(Z-piperidlnoethyl)-fl-phenylethanol hydrochloride thusprepared crystallized as white needles which melted at about 234--237 C.Analysis showed the presence of 4.09 percent nitrogen as compared withthe calculated value of 4.06 percent.

a-(2-piperidinoethyl)-stilbene is prepared by the dehydration ofa-phenyl-a-(z-piperidinoethyD-fi-phenyIethanQI hydrochloride withhydrochloric acid as follows:

g. (0.5 mol) of oz-PhEIlYl-a-(Z-DlDGIldlIlO- ethyl) -;3-phenylethanolhydrochloride are re fluxed for 2 hours with 825 cc. 10 mols) of 12Nhydrochloric acid. On cooling to room temperaturem-(2-piperidinoethyl)-sti1bene hydrochloride crystallizes out and isfiltered off, washed with acetone and anhydrous ether. The filtrate isconcentrated to about 500 cc. in vacuo and 350 cc. of 12N hydrochloricacid are added and the solution refluxed 2 hours. Upon cooling, anadditional amount of a-(2-piperidinoethyl) -stilbene hydrochlorideseparates as an oil. The oil is removed and treated with acetone,whereupon the a-(2 piperidinoethyl) stilbene crystallizes. A repetitionof the concentration of the filtrate and addition of more acid andrefluxing yields an additional amount of the desired product. Theprecipitates are combined and recrystallized from boiling absoluteethanol, yielding a-(2-piperidinoethyl) -stilbene hydrochloride whichmelts with decomposition at about 243-244" C.

a-(2 piperidinoethyl) stilbene hydrochloride may also be prepared bydehydration of a-phenyla-(2 piperidinoethyl) fl phenylethanolhydrochloride with phosphorus tribromide as follows:

60 g. (0.2 mol) of a-phenyl-a-(2-piperidinoethyl) -fl-phenylethanolhydrochloride are suspended in 500 cc. of chloroform and 70 cc. (200 g.,0.75 mol) of phosphorus tribromide are added. After minutes thehydrochloride salt is dissolved, forming a clear solution which isallowed to stand at room temperature for about 8 hours. The chloroformis then removed by evaporation on a steam bath and the residue isdissolved in 200 cc. of water. The water solution is made stronglyalkaline with sodium hydroxide and extracted 3 times with 100 cc.portions of acetone-ether mixture (1:20). The cooled ether solution istreated with dry hydrogen chloride, whereupon white crystals ofa-(2-piperidinoethyl)-stilbene hydrochloride separate. The crystals arefiltered off and recrystallized from ethanol-ether solution yieldinga-(2-piperidinoethyl) -stilbene hydrochloride which melts withdecomposition at about 243-244 C.

a-(z-piperidinoethyl) -stilbene is prepared from its hydrochloride saltby dissolving the hydrochloride salt in about 10 times its amount ofwater and making the solution alkaline with sodium hydroxide solution.The rpm-piperidinoethyl)- stilbene which separates as an oil isextracted with ether, the ether solution dried and the a-(2-piperidinoethyl) -stilbene is isolated by evaporation of the ether invacuo.

Example 2 Preparation of a-(2-piperidinoethyl) -4-methoxystilbenehydrochloride.

85 g. of p-methcxyphenyl-p-piperidinoethyl ketone (prepared according tothe method of Mannich and Lammering as set forth in Example 1) aredissolved in 200 cc. of water, the solution is made strongly alkalinewith sodium hydroxide and extracted three times with 200 cc. of ether.The combined ether extracts containing thepmethoxyphenyl-p-piperidinoethyl ketone base are dried with anhydrousmagnesium sulfate, and added to a Grignard reagent prepared from 17 g.of magnesium and 20 g. of benzyl chloride in 500 cc. of anhydrous ether.The mixture is stirred for about 2 hours at room temperature and ispoured into a mixture of 170 cc. of 12N hydrochloric acid and 150 g. ofice whereupon a white precipitate ofa-p-methoxyphenyl-a-(Z-piperidinoethyl) -B-phenylethanol hydrochlorideforms. The precipitate is filtered off and recrystallized fromether-alcohol whereupon it melts at about 235-237 C. (dec.). 1

The a-p-methoxyphenyl-a- (2-piperidinoethyl) B-phenylethanolhydrochloride so prepared is dehydrated with hydrochloric acid accordingto the 8 procedure set forth in Example 1. a-(2-piperidinoethyl) 4methoxystilbene hydrochloride melts at about 234-235 C.

a- (2-piperidinoethyl) -4-methoxystilbene may be obtained from itscorresponding hydrochloride salt by the procedure described in Example1.

Example 3 Preparation of a-(2-piperidinoethyl) -4-chlorostilbenehydrobromide.

A mixture of 78 g. of p-chloroacetophenone, 60 g. of piperidinehydrochloride, 2 cc. of 12N hydrochloric acid, 22.5 g. ofparaformaldehyde and 150 cc. of absolute alcohol is refluxed for onehour. 15 g. of paraformaldehyde are added and refiuxing is continued fortwo hours. The mixture is then poured into 1200 cc. of hot acetone. Theacetone solution is cooled to about 0 C. and thew-piperidino-p-chloropropriophenone hydrochloride which separates incrystalline form is filtered off. The crystals melt at about 190-193 C.

69 g. of w-piperidino-p-chloropropriophenone base dissolved in 300 cc.of anhydrous ether are added to a Grignard reagent prepared from 17 g.of magnesium and g. of benzyl chloride in 500 cc. of anhydrous ether.The mixture is stirred for two hours at room temperature and is thenpoured into a mixture of 180 cc. of 12N hydrochloric acid and g. of ice.The white precipitate of a-pchlorophenyl-a-(2-piperidinoethyl) pphenylethanol hydrochloride which forms is filtered ofl. Afterrecrystallization from ether-alcohol mixture it melts at about 246-248C.

The a-p-chlorophenyl-a- (Z-piperidinoethyl) phenylethanol hydrochlorideis dehydrated with phosphorus tribromide by the method set forth inExample 1. 25 g. of the carbinol and 57 g. of phosphorus tribromide,dissolved in 200 cc. of chloroform, are allowed to stand for about 8hours. Most of the chloroform is then removed by evaporation in vacuoand the residue is taken up in an excess of absolute ethanol. Thesolution is poured into 200 cc. of water, the mixture made stronglyalkaline with sodium hydroxide and extracted three times with cc.portions of ether. The combined ether extracts are dried over magnesiumsulfate and the ether is removed by evaporation in vacuo. The resultingresidue is dissolved in a mixture of 500 cc. of 1:1 absoluteethanol-acetone containing 20 cc. of 48 percent hydrobromic acid. Etheris added to the solution to incipient crystallization and the solutionis then cooled, substantially completing the crystallization ofa-(2-piperidinoethyl) -4-chlorostilbene hydrobromide. The crystals arefiltered off and purified by precipitation from ethanol solution by theaddition of ether. a-(2-piperidinoethyl) -4-chlorostilbene hydrobromidemelts at 207-208.5 C.

a- (2-piperidinoethyl) -4-chlorostilbene may be prepared from itshydrobromide salt by the procedure described in Example 1.

Example 4 prepared melts at about 240-241 0. Analysis showed thepresence of 4.73 percent nitrogen as compared with the calculated valueof 4.25 percent.

The a-phenyl-e- (2-morpholinoethyl) -3-phenylethanol hydrochloride isdehydrated with phosphorus tribromide according to the process describedin Example 1. White crystals of a-(Z- morpholinoethyl) -stilbenehydrochloride, melting at about 239-241 C. are obtained.

a-(2-morpholinoethyl)-stilbene may be prepared from its hydrochloridesalt by the procedure described in Example 1.

Example 5 Preparation of a-(2-piperldinoethyl) -4-methylstilbenehydrobromide.

69 g. of phenyl-(p-piperidino) -ethyl ketone, prepared by the method ofExample 1, are dissolved in 300 cc. of anhydrous ether and the solutionis added to a Grignard reagent prepared from 17 g. of magnesium and 101g. of p-xylyl chloride and 500 cc. of anhydrous ether. The mixture isstirred for two hours at room temperature and then poured into a mixtureof 170 cc. of 12N hydrochloric acid and 100 g. of ice. The precipitateof a-phenyl-a-(2-piperidinoethyl)-18- xylylethanol hydrochloride whichforms is filtered oil. Upon recrystallization from ether-alcoholsolution it melts at about 248 C. (dec.). The dehydration ofa-phenyl-a-(Z-piperidinoethyl) 43- xylylethanol hydrochloride isaccomplished with phosphorus tribromide by the method set forth inExample 1. a-(2-piperidinoethyl) -4'-methylstilbene hydrobromide isprepared by treating an ethereal solution of a-(2-piperidinoethyl) -4'-methylstilbene with anhydrous hydrogen bromide and uponrecrystallization from ether-alcohol the hydrobromide salt melts atabout 209-210" C.

Example 6 a-[2 (methyl-n-propylamino) ethyll-stilbene hydrobromide.

The procedure of Example 1 is repeated using 83 g. ofmethyl-n-propylamine, 2 cc. of 12N hydrochloric acid, 34 g. ofparaformaldehyde, 90 g. of acetophenone and 210 cc. of absolute ethanol,with subsequent addition of 23 g. of paraformaldehyde. The resultingphenyl-2-(methyln-propylamino) -ethyl ketone hydrochloride isrecrystallized from ether-alcohol solution whereupon it melts at 148-149C.

A solution of 72.5 g. of phenyl-2-(methyl-npropylamino)-ethyl ketone in300 cc. of anhydrous ether is reacted with a Grignard reagent preparedfrom 17 g. of magnesium, 90 g. of benzyl chloride and 500 cc. ofanhydrous ether, according to the method described in Example 1. The a.-phenyl-:; (2-methyl-n-propylamino-ethyl) phenylethanol hydrochloridethus prepared melts at 94-95 C. Analysis showed the presence of 4.22percent nitrogen as compared with the calculated value of 4.19 percent.

The dehydration ofa-phenyl-e-(z-methyl-npropylamino-ethyl)-p-phenylethanol hydrochlorideis effected by the use of phosphorus tribromide by the proceduredescribed in Example 1. The a-[2-(methyl-n-propylamino) ethyl] -stilbeneso produced is precipitated from anhydrous ether solution with hydrogenbromide yielding a [2 (methyl-n-propylamino) -ethyl] stilbenehydrobromide. After recrystallization from etheralcohol the hydrobromidesalt melts at 167-168 C.

I claim:

1. A compound selected from the group consistlng of substitutedstilbenes and their acid addition salts, said stilbenes beingrepresented by the formula R1-C=C-R| Hail CH:

and acid addition salts thereof.

3. a- (2-piperidinoethyl) -sti1bene. 4. a- (2-piperidinoethy1) 4methoxystilbene represented by the formula H1 H, c H:

and acid addition salts thereof.

5. u-(2-piperidinoethyl) -4-methoxystilbene. 6. a-(2-piperidinoethyl) -4chlorostilbene represented by the formula O CH:

and acid addition salts thereof.

7. a-(2-P1PB1idlI108thYl) -4-chlorostilbene.

EWALD ROHRMANN.

REFERENCES CITED The following references are of record in the a file ofthis patent:

UNITED STATES PATENTS

